Changes in neuronal intrinsic excitability (IE) might be crucial mechanisms for memory formation in the hippocampus. Many studies have demonstrated that long-term potentiation of IE (LTP-IE) is associated with behavioral learning and that changes in neuronal excitability accompany memory disorders associated with aging and chronic stress. Thus, understanding LTP-IE might be vital to clarifying how changes in hippocampal circuit function underly some cognitive disorders. Despite these findings, the cellular and molecular mechanisms of this type of plasticity are not well understood. Additionally, little is known about how LTP-IE might interact with and regulate synaptic forms of plasticity such as LTP and LTD. We have recently discovered a novel stimulation protocol that selectively induces LTP-IE in the absence of synaptic potentiation in the CA1 region of the mouse hippocampus. Using this stimulation protocol, we plan to use extracellular and whole-cell electrophysiological recordings combined with pharmacological manipulations to investigate: 1. The cellular basis of LTP-IE: We will use dendritic patch-clamp recordings to test the hypothesis that LTP-IE is due to a localized increase in dendritic excitability, resulting in enhanced propagation of depolarizing currents along CA1 pyramidal neuron dendrites. 2. The molecular mechanisms of LTP-IE: We will use pharmacological blockers of protein kinases paired with electrophysiological recordings to test the prediction that LTP-IE results from PKA, PKC, or CaMKII activation. 3. The functional importance of LTP-IE: We will use electrophysiological recordings to test the hypothesis that LTP-IE facilitates synaptic LTP and LTD. Relevance of Research to Public Health: The experiments proposed here are directly relevant to the mission of the NIMH, because they will provide novel information about how the hippocampus, a part of the brain vital to learning and memory processes, functions at a molecular, cell and circuit level. This information can then be used to directly test how the cell and network physiology of the hippocampus is affected in cognitive disorders. Discovering how hippocampal functioning is disrupted in neurological, mood, and cognitive disorders can allow the development of more effective targeted therapies. [unreadable] [unreadable] [unreadable]